title: Internalization of oncolytic reovirus by human dendritic cell carriers protects the virus from neutralization.
abstract: OBJECTIVE
  Dendritic cells (DC) may be the most effective way of delivering oncolytic viruses to patients. Reovirus, a naturally occurring oncolytic virus, is currently undergoing early clinical trials; however, intravenous delivery of the virus is hampered by pre-existing antiviral immunity. Systemic delivery via cell carriage is a novel approach currently under investigation and initial studies have indicated its feasibility by using a variety of cell types and viruses. This study addressed the efficacy of human DC to transport virus in the presence of human neutralizing serum.
  
  
  METHODS
  Following reovirus-loading, DC or T cells were cocultured with melanoma cells with or without neutralizing serum; the melanoma cells were then analyzed for cell death. Following reovirus loading, cells were examined by electron microscopy to identify mechanisms of delivery. The phagocytic function of reovirus-loaded DC was investigated by using labeled tumor cells and the ability of reovirus-loaded DC to prime T cells was also investigated.
  
  
  RESULTS
  In the presence of human neutralizing serum DC, but not T cells, were able to deliver reovirus for melanoma cell killing in vitro. Electron microscopy suggested that DC protected the virus by internalization, whereas with T cells it remained bound to the surface and hence accessible to neutralizing antibodies. Furthermore, DC loaded with reovirus were fully functional with regard to phagocytosis and priming of specific antitumor immune responses.
  
  
  CONCLUSIONS
  The delivery of reovirus via DC could be a promising new approach offering the possibility of combining systemic viral therapy for metastatic disease with induction of an antitumor immune response.
authors.affiliation: Cancer Research UK, Leeds Institute of Molecular Medicine, St James' University Hospital, Leeds, United Kingdom.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Ilett
authors.forename: Montserrat
authors.initials: M
authors.lastname: Bárcena
authors.forename: Fiona
authors.initials: F
authors.lastname: Errington-Mais
authors.forename: Stephen
authors.initials: S
authors.lastname: Griffin
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Harrington
authors.forename: Hardev S
authors.initials: HS
authors.lastname: Pandha
authors.forename: Matthew
authors.initials: M
authors.lastname: Coffey
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Selby
authors.forename: Ronald W A L
authors.initials: RW
authors.lastname: Limpens
authors.forename: Mieke
authors.initials: M
authors.lastname: Mommaas
authors.forename: Rob C
authors.initials: RC
authors.lastname: Hoeben
authors.forename: Richard G
authors.initials: RG
authors.lastname: Vile
authors.forename: Alan A
authors.initials: AA
authors.lastname: Melcher
mesh_terms: D057134:Antibodies, Neutralizing / Q000009:adverse effects*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology / Q000821:virology*; D004337:Drug Carriers; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D008545:Melanoma / Q000473:pathology / Q000628:therapy; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000378:metabolism* / Q000502:physiology; D012087:Reoviridae / Q000378:metabolism / Q000502:physiology*; D012878:Skin Neoplasms / Q000473:pathology / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D016896:Treatment Outcome; D019562:Viral Load / Q000502:physiology; D053586:Virus Internalization
chemical_list: D057134:Antibodies, Neutralizing; D004337:Drug Carriers